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Engineering alpha fetoprotein and glypican-3 to develop hepatoma (HCC) vaccines

改造甲胎蛋白和磷脂酰肌醇蛋白聚糖 3 以开发肝癌 (HCC) 疫苗

基本信息

批准号：
9231438
负责人：
YUKAI HE
金额：
$ 32.06万
依托单位：
AUGUSTA UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-04-01 至 2019-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9231438
关键词：
Adjuvant Adjuvant Therapy Adverse effects Aftercare Animal Model Antigens Autoimmune Hepatitis CD4 Positive T Lymphocytes CD8B1 gene Cancer Etiology Cancer Vaccines Carcinogens Cells Cessation of life Computational algorithm Data Dendritic Cells Development Diabetes Mellitus Diethylnitrosamine Engineering Epitopes Excision Fright GPC3 gene Generations Goals Hepatitis B Hepatitis B Surface Antigens Hepatitis B Vaccines Hepatitis C Hepatitis C Prevalence Hepatocyte Human Immune Immune Targeting Immune Tolerance Immune system Immunization Immunologic Surveillance Incidence Individual Infection Lead Legal patent Liver Malignant Neoplasms Malignant neoplasm of liver Modeling Mono-S Mus Obesity Operative Surgical Procedures Outcome Patient risk Patients Prevention Primary carcinoma of the liver cells Proteins Recombinants Recurrence Relapse Risk Factors Survival Rate T cell response T memory cell T-Lymphocyte Testing Therapeutic Studies Tissues Transgenic Organisms Transplantation Tumor Antigens United States Vaccines Virus-like particle Work alpha-Fetoproteins antitumor effect design exhaustion fighting high risk high risk population immune activation immunogenic immunogenicity innovation killings melanoma memory CD4 T lymphocyte mouse model neoplastic cell novel novel strategies novel therapeutics pre-clinical prevent public health relevance response success tumor vaccine efficacy vaccine evaluation vaccinia virus vector

项目摘要

DESCRIPTION (provided by applicant): Liver cancer is the 5th most common cancer (748,000 cases a year) and the 3rd most common cause of cancer death (695,000 deaths a year) in the world. In the United States, while the incidence of many major cancers is declining, the incidence of hepatocellular carcinoma (HCC), the most common type of liver cancer, has almost tripled over the past two decades to ~20,000 per year. Despite the success of HBV vaccines to prevent new HBV infection, the large pool of existing HBV (350 million) and HCV (170 million) patients and the recent recognition that obesity/diabetes become a major risk factor of HCC in US suggest that HCC incidence will continue increasing over next few decades. Unfortunately, treatment options for HCC are limited, contributing to the dismal 17% 3-year survival rate. Liver resection and transplantation are curative for small tumors. But, the lac of adjuvant treatments after surgery is a critical barrier to the success of liver resection, which results in ~70% 5-year recurrence rate. Thus, there is an urgent need to develop novel approaches for HCC. Our long-term goal is to develop HCC vaccines to activate patient's immune system to conduct immune surveillance and thereby prevent HCC relapse or de novo development in high risk population. Approximately 84% of HCC (but not normal hepatocytes) express alpha fetoprotein (AFP), glypican 3 (GPC3), or both, making them excellent immune targets. However, they are self/tumor antigens and weakly immunogenic, and thus cannot effectively activate immune cells to generate significant antitumor effect. In this application, we propose to use murine autochthonous models to test the hypotheses that innovative approach of antigen engineering will increase the immunogenicity of HCC-associated self/tumor antigens of AFP and GPC3 to create effective HCC vaccines and that novel immunization strategy with the engineered HCC vaccines will induce potent and highly responsive memory T cells that conduct immune surveillance to prevent autochthonous HCC. The objectives are 1) to create immunogenic HCC vaccines, 2) to establish effective immunization strategy, and 3) to prevent autochthonous HCC. The outcomes will be the effective activation of immune system to prevent autochthonous HCC and generation of critical preclinical data that will help development of human HCC vaccine, which eventually lead to new therapy to fill the gap of HCC management after surgery. This will greatly benefit HCC patients who have undergone liver resection by preventing relapse and also offer an attractive option to prevent HCC de novo development in high risk populations who are living in the fear of developing HCC. This will bring about a radical change of HCC management, shifting the focus of cancer vaccine research from therapy to prevention, which is what a vaccine does best.

描述（由申请人提供）：肝癌是世界上第五大最常见的癌症（每年748,000例）和第三大最常见的癌症死亡原因（每年695,000例）。在美国，虽然许多主要癌症的发病率正在下降，但最常见的肝癌类型肝细胞癌（HCC）的发病率在过去二十年中几乎增加了两倍，达到每年约20,000例。尽管HBV疫苗在预防新发HBV感染方面取得了成功，但现有的大量HBV（3.5亿）和HCV（1.7亿）患者，以及最近认识到肥胖/糖尿病成为美国HCC的主要危险因素，表明HCC发病率在未来几十年将继续增加。不幸的是，HCC的治疗选择有限，导致其3年生存率仅为17%。肝切除和肝移植是治疗小肿瘤的有效方法。但是，术后辅助治疗的缺失是肝切除术成功的关键障碍